The massively parallel computation of absolute binding free energy with a
well-equilibrated system (MP-CAFEE) has been developed [H. Fujitani, Y. Tanida,
M. Ito, G. Jayachandran, C. D. Snow, M. R. Shirts, E. J. Sorin, and V. S.
Pande, J. Chem. Phys. 123, 084108 (2005)]. As an application, we
perform the binding affinity calculations of six theophylline-related ligands
with RNA aptamer. Basically, our method is applicable when using many compute
nodes to accelerate simulations, thus a parallel computing system is also
developed. To further reduce the computational cost, the adequate non-uniform
intervals of coupling constant λ, connecting two equilibrium states,
namely bound and unbound, are determined. The absolute binding energies ΔG thus obtained have effective linear relation between the computed and
experimental values. If the results of two other different methods are
compared, thermodynamic integration (TI) and molecular mechanics
Poisson-Boltzmann surface area (MM-PBSA) by the paper of Gouda etal [H.
Gouda, I. D. Kuntz, D. A. Case, and P. A. Kollman, Biopolymers 68, 16
(2003)], the predictive accuracy of the relative values ΔΔG is
almost comparable to that of TI: the correlation coefficients (R) obtained are
0.99 (this work), 0.97 (TI), and 0.78 (MM-PBSA). On absolute binding energies
meanwhile, a constant energy shift of ∼ -7 kcal/mol against the
experimental values is evident. To solve this problem, several presumable
reasons are investigated.Comment: 23 pages including 6 figure